Alzheimer's disease (AD) is a common and devastating illness for which there is no effective therapy. Increasing evidence suggests that brain oxidative stress is an early feature of AD. The brains of a fully evolved AD are characterized by senile plaques (SPs) formed by fibrillar amyloid beta (Abeta), neurofibrillary tangles (NFTs) formed by paired helical filaments assembled from hyper-phosphorylated tau (PHF-tau), and more than 50% also show accumulation of Lewy bodies (LBs) formed by aggregated alpha-synuclein (AS). In addition to these lesions, the AD brain exhibits evidence of extensive oxidative damage, which manifests predominantly as lipid peroxidation since this organ is rich in polyunsaturated fatty acids. F2-isoprostanes (F2-iPs) are specific and sensitive markers of lipid peroxidation in vivo. We have shown that a major F2-iP, 8,12-iso-iPF2alpha-VI, is increased in AD but not in other neurodegenerative diseases, where it correlates with disease severity. This observation raises the possibility that it may be a useful biomarker to monitor brain oxidative damage in AD. Based on in vitro studies, the accumulation of fibrillar Abeta 1-40/42 into SPs is thought to be a central event in the pathogenesis of AD and responsible for the increase in brain oxidative stress. However, no data are available on the contribution of the other hallmark lesions of the disease to this phenomenon. The long-term goal of Project 3 is to determine the role that each of these lesions, alone or in the presence of Abeta 1-40/42, plays in AD with particular emphasis on lipid peroxidation. In addition, while the mechanisms that convert normal Abeta into insoluble filaments that aggregate into SPs are poorly understood, oxidative stress has been implicated as a positive feed-back mechanism. In addition, Project 3 we will test the hypothesis that oxidative stress, by producing specific F2-iP, modulates the production of these peptides and/or alter their biophysical properties thereby converting them into insoluble filaments. Completion of this project will lead to new insights into mechanisms of AD as well as identify potential therapeutic targets for treating this devastating disease.